Cationic antiprotozoal drugs. Trypanocidal activity of 2-(4'-formylphenyl)imidazo[1,2-a]pyridinium guanylhydrazones and related derivatives of quaternary heteroaromatic compounds.
A series of quaternary 2-phenylimidazo[1,2-a]pyridinum salts has been prepared and evaluated for antiparasitic activity. Primary attention was focused on derivatives with amido, substituted hydrazone, and heterocyclic functionality at the para position of the phenyl substituent. Guanylhydrazones and N-substituted guanylhydrazones of the 4'-formyl-substituted compounds are very active against the blood state Trypanosoma rhodesiense in mice by subcutaneous or oral administration. The most potent compounds attain 100% survival for 30 days at doses of less than 1.0 mg/kg (sc) and greater than 5.0 mg/kg (po). Weaker activity is noted for certain other 4'-substituents such as carboxamidines and carboxamide oximes. Considerable variation in structure, including replacing of the imidazo [1,2-a]pyridinium ring by other cationic heterocyclic rings and insertion of linking groups between the heterocyclic ring and phenyl group, can be done, and a high level of activity is maintained. Relationships between these structural changes and biological activity are discussed.
Sundberg
R J
RJ
Department of Chemistry, University of Virginia, Charlottesville 22901.
Dahlhausen
D J
DJ
Manikumar
G
G
Mavunkel
B
B
Biswas
A
A
Srinivasan
V
V
Musallam
H A
HA
Reid
W A
WA
Ager
A L
AL
D000818:Animals; D002412:Cations; D055598:Chemical Phenomena; D002621:Chemistry; D006151:Guanosine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology / Q000627:therapeutic use; D006835:Hydrazones / Q000138:chemical synthesis / Q000494:pharmacology / Q000627:therapeutic use*; D007093:Imidazoles / Q000138:chemical synthesis / Q000494:pharmacology / Q000627:therapeutic use*; D007930:Leucine / Q000378:metabolism; D015394:Molecular Structure; D011726:Pyridinium Compounds / Q000138:chemical synthesis / Q000494:pharmacology / Q000627:therapeutic use*; D013329:Structure-Activity Relationship; D013936:Thymidine / Q000378:metabolism; D014344:Trypanocidal Agents; D014346:Trypanosoma brucei brucei / Q000187:drug effects / Q000378:metabolism; D014352:Trypanosomiasis / Q000188:drug therapy
D002412:Cations; D006835:Hydrazones; D007093:Imidazoles; D011726:Pyridinium Compounds; D014344:Trypanocidal Agents; D006151:Guanosine; D007930:Leucine; D013936:Thymidine